Regioselective Research Articles

Muon Spin Rotation (μSR) for Characterizing Radical Addition to C=S in Xanthene-9-thione and Thioxanthene-9-thione

Abstract Muonium (μ+e−) can be produced by capture of an electron by a spin-polarized muon (μ+) and has been utilized as a light isotope of hydrogen. In this paper, we demonstrate muon spin rotation (μSR) experiments and preliminary computational analyses of the regioselective muonium addition to xanthene-9-thione and thioxanthene-9-thione providing the C-centered radicals. The transverse-field muon spin rotation (TF-μSR) experiments of the cyclic thioketones revealed considerable increase of muon hyperfine coupling constants (muon hfc, Aμ) compared with the muoniated thiobenzophenone, indicating crucial roles of the bridging chalcogen atom promoting the overlap between the S–Mu bond orbital and the radical p orbital.

Molecular and silica-supported metal complexes as new catalysts for hydrosilylation

Two disiloxanes with pyridyl or isocyanide functional groups, as well as silica materials carrying pyridyl or thiol functionalities were used as ligands for Pt(IV) and Fe(III) ions. The molecular and silica-supported metal complexes were tested in a model hydrosilylation reaction between 1,3-divinyl tetramethyldisiloxane and 1,1,3,3-tetramethyldisiloxane, conducted in (pseudo)-heterogeneous conditions. The new hydrosilylation catalysts afforded 75-100 % conversion and 87-93 % selectivity, based on NMR data, while some of them presented recyclability; they were also successful in silicones crosslinking at room temperature. In particular, the iron-isocyanide disiloxane complex is proposed as a promising, cheap, unsophisticated and stable catalyst, capable to act in heterogeneous conditions, without the need of dry solvent or inert atmosphere. Silica-supported Pt or Pt/Pd catalysts, obtained with commercial or recovered noble metals precursors, presented high conversion and increased regioselectivity in the hydrosilylation reaction, being reusable, and are efficient in other hydrosilylation reactions, useful in organic and silicon chemistry.

Regioselective Derivatization of Silylated [20]Silafulleranes

Silafulleranes with endohedral Cl- ions are a unique, scarcely explored class of structurally well-defined silicon clusters and host-guest complexes. Herein, we report regioselective derivatization reactions on the siladodecahedrane [nBu4N][Cl@Si20(SiCl3)12Cl8] ([nBu4N][1]), which has its cluster surface decorated with 12 SiCl3 and 8 Cl substituents in perfect Th symmetry. The room-temperature reaction of [nBu4N][1] with excess iBu2AlH in ortho-difluorobenzene (oDFB) furnishes perhydrogenated [nBu4N][Cl@Si20(SiH3)12H8] ([nBu4N][2]) in 50% yield; the non-pyrophoric [2]- is the largest structurally authenticated (by X-ray diffraction) hydridosilane known to date. A simple switch from pure oDFB to an oDFB/Et2O solvent mixture suppresses core hydrogenation and results in the formation of [nBu4N][Cl@Si20(SiH3)12Cl8] ([nBu4N][3]). In addition to the exhaustive Cl/H exchange at all 44 Si-Cl bonds of [1]- and the regioselective 36-fold silyl group hydrogenation, we achieved the simultaneous introduction of Me substituents at all 8 SiCl vertices along with the conversion of all 12 SiCl3 to SiH3 groups by treating [nBu4N][1] with Me2AlH/Me3Al in oDFB ([nBu4N][Cl@Si20(SiH3)12Me8], [nBu4N][4]; 73%). Quantum-chemical free-energy calculations find an SN2-Si-type hydrogenation of the exohedral SiCl3 moieties in [1]- (trigonal-bipyramidal intermediate) slightly preferred over metathesis-like SNi-Si substitutions (four-membered transition state). Cage hydrogenation likely occurs via SNi-Si processes. The experimentally demonstrated influence of an Et2O co-solvent, which drastically increases the respective reaction barriers, is attributed to the increased stability of the resulting iBu2AlH-OEt2 adduct and its higher steric bulk compared to free iBu2AlH.

Triazine Chalcogenones from Thiocyanate or Selenocyanate Addition to Tetrazine Ligands in Ruthenium Arene Complexes.

The chemistry of 1,2,4,5-tetrazines has attracted considerable interest both from a synthetic and applicative standpoint. Recently, regioselective reactions with alkynes and alkenes have been reported to be favored once the tetrazine ring is coordinated to Re(I), Ru(II), and Ir(III) centers. Aiming to further explore the effects of metal coordination, herein, we unveil the unexplored reactivity of tetrazines with chalcogenocyanate anions. Thus, ruthenium(II) tetrazine complexes, [RuCl{κ2N-3-(2-pyridyl)-6-R-1,2,4,5-tetrazine}(η6-arene)]+ (arene = p-cymene, R = H, [1a]+, R = Me, [1b]+, R = 2-pyridyl, [1c]+; arene = C6Me6, R = H, [1d]+, R = Me, [1e]+; PF6- salts), reacted quantitatively and in mild conditions with M(ECN) salts (M = Na, K, Bu4N; E = O, S, Se). The addition of thiocyanate or selenocyanate to the tetrazine ligand is regioselective and afforded, via N2 release, 1,2,4-triazine-5-chalcogenone heterocycles, the one with selenium being unprecedented. The novel ruthenium complexes [RuCl{κ2N-(2-pyridyl)}{triazine chalcogenone}(η6-arene)] 2a-e (sulfur), 3b, 3d, and 3e (selenium) were characterized by analytical (CHNS analyses, conductivity), spectroscopic (IR, multinuclear and two-dimensional (2D) NMR), and spectrometric (electrospray ionization mass spectrometry (ESI-MS)) techniques. According to density functional theory (DFT) calculations, the nucleophilic attack of SCN- on the tetrazine ring is kinetically driven. Compound 2b is selectively and reversibly mono-protonated on the triazine ring by HCl or other strong acids, affording a single tautomer. When reactions of chalcogenocyanates were performed on the 2,2'-bipyridine (bpy) complex [RuCl(bpy)(η6-p-cymene)]+, the chloride substitution products [Ru(ECN)(bpy)(η6-p-cymene)]+ (E = O, [4]+; E = S, [5]+; E = Se, [6]+) were obtained in 82-90% yields (PF6- salts). Combined spectroscopic data (IR, 1H/13C/77Se NMR) was revealed to be a useful tool to study the linkage isomerism of the chalcogenocyanate ligand in [4-6]+.

Effective Organotin-Mediated Regioselective Functionalization of Unprotected Carbohydrates

Regioselective functionalization of unprotected carbohydrates at a secondary OH group in the presence of primary OH groups based on the commonly used organotin-mediated reaction has been improved. We found that the preactivation of the dibutylstannylene acetal intermediate with tetrabutylammonium bromide in toluene is a key to the improved condition for the efficient, high-yielding, and regioselective tosylation, benzoylation, or benzylation of unprotected carbohydrates. The counteranion of tetrabutylammonium ion with a weak coordination ability plays a crucial role in the improved regioselective reactions. A convenient access to the intermediates of synthetic value is also demonstrated in the organotin-mediated regioselective tosylation of unprotected carbohydrates, followed by the nucleophilic inversion reaction to give sulfur-containing and azide-modified carbohydrates.

Novel bipyrazole and pyrazolopyridazinone derivatives via regioselective cycloaddition reaction of nitrilimines to enaminone: Synthesis and structural elucidation

1-(3,5-Dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl)-3-(dimethylamino)prop‑2-en-1-one 2 was prepared by refluxing of 1-(3,5-dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl)ethan-1-one 1 with dimethylformamide dimethyl acetal (DMF-DMA). Heating of enaminone 2 with hydrazonoyl halides 3a–h or C-alkoxy carbonylhydrazonoyl chlorides 3i-p in chloroform in the presence of triethylamine afforded novel bipyrazole derivatives 4a–h or 9i-p. The structures of compounds 9i-p were confirmed chemically via their conversion to pyrazolopyridazinones 11i-m upon the reaction with hydrazine hydrate in refluxing ethanol. Moreover, the structures of the novel bipyrazoles and pyrazolopyridazinones were confirmed via spectral data and elemental analyses, in addition to single-crystal X-ray diffraction.

Organocatalytic Regioselective Chloro‐sulfonylation of Mono‐ and 1,2‐Disubstituted Epoxides by Using 4‐Methylpyridine N‐Oxide

AbstractA highly regioselective organocatalytic chlorosulfonylation reaction for terminal epoxides is developed. The method uses various sulfonyl chloride reagents, such as MsCl or TsCl, and is catalyzed with 4‐methylpyridine N‐oxide. Several sulfonylated halohydrins are obtained with reasonable to high regioselectivity and the reaction is applied to 1,2‐disubstituted epoxides.

Regioselective syntheses of 2-oxopyridine carbonitrile derivatives and evaluation for antihyperglycemic and antioxidant potential

A library of 2-oxopyridine carbonitriles 1–34 was synthesized by regioselective nucleophilic substitution reactions. In the first step, a one-pot multicomponent reaction yield pyridone intermediates. The resulting pyridone intermediates were then reacted with phenacyl halides in DMF and stirred at 100 °C for an hour to afford the desired compounds in good yields. Structures of synthetic molecules were characterized by EI-MS, HREI-MS, 1H NMR, and 13C NMR, and all thirty-four (34) compounds were found to be new. All synthetic compounds were examined for antidiabetic and antioxidant potential. The compounds exhibited α-glucosidase inhibitory potential in the range of IC50 = 3.00 ± 0.11–43.35 ± 0.67 μM and α-amylase inhibition potential in the range of IC50 = 9.20 ± 0.14–65.56 ± 1.05 μM. Among the tested compounds, 1 showed the most significant α-glucosidase inhibitory activity, with an IC50 value of 3.00 ± 0.11 μM, while the most active compound against α-amylase was 6, with an IC50 value = 9.20 ± 0.14 μM. The kinetic studies and analysis indicated that the compounds followed the competitive mode of inhibition. In addition, the molecular docking studies showed the interaction profile of all molecules with the binding site residues of α-glucosidase and α-amylase enzymes.

Recent Progress in Arylmetalative Cyclization/Annulation of Functionalized Alkynes with Organoboranes

AbstractAchieving complex molecular assemblies in modular modes is always one of the top priorities of the organic chemist. Cyclization/annulation of functionalized alkynes through carbo metalation has an impactful swath in synthetic organic chemistry. There have recently been considerable contributions in this arena uncovering several new chemical spaces towards new solutions for various fields of biology. On the other hand, organoboronic reagents are fascinating reactive chemprobs, are partake in a broad range of chemical transformations. Particularly utility of these reagents in the carbo‐metalation of alkynes is the subject of high perusal in organic chemistry. To this degree, tuning various transition‐metal catalysts with organoboranes and functionalized alkynes is an intriguing subject for the synthesis of various classes of acyclic and cyclic adducts. Mechanistically, these arylative cyclizations proceed through initial aryl‐metalation on alkynes which provides alkenyl metal species, that concomitantly react with the pendent electrophile. The stereo‐ and regioselective reactivity of this C‐metal is steered by chelation with the coordinating group and/or electrophile on alkyne. In this review, we focused on the critical achievements of the field with the emphasis on the stereoselective capture of the vinyl metal complex with a pendent electrophile. In this field, compilation of the detailed mechanistic pathways in this realm would be helpful to find the gaps and hence to discover novel transformations.

Angular Regioselective Synthesis of Varied Functionalized Hexahydro-1,2,4-triazolo[4,3-a]quinazolin-9-ones and Their Antiproliferative Action.

New 2-thioxopyrimidin-4-ones capable of participating in regioselective reactions with functionally diverse hydrazonoyl chlorides towards angular regioisomers, rather than linear ones, were designed and synthesized to form stereoisomeric cis- and trans-hexahydro [1,2,4]triazolo[4,3-a]quinazolin-9-ones to be tested as antitumor candidates. The angular regiochemistry of the products was verified through crystallographic experiments and NMR studies. In addition, the regioselectivity of the reaction was found to be independent of the stereochemistry of the used 2-thioxopyrimidin-4-one. Only compound 4c demonstrated satisfactory growth inhibition against all the cancer cells used among all the produced drugs.

Highly Regioselective Propargylation/Allenylation of Organolanthanum Reagents with Aldehydes.

The metal-mediated propargylation or allenylation of carbonyl compounds is well-adapted to the preparation of homopropargylic or allenylic alcohols, which are multifunctional intermediates in synthetic chemistry. However, the regioselectivity of reactions using propargyl or allenyl metal reagents is difficult to control, owing to the equilibrium between the two species. In our study, propargyl or allenyl organolanthanum reagents were prepared using trimethylsilylpropyne or prop-1-yn-1-ylbenzene substrates. The treatment of the organolanthanum reagents with aldehydes yielded the regioselective products, respectively. This study provides a better understanding of structural specificity and the special chemoselectivity of rare earth metal reagents.

Exposed Zinc Sites on Hybrid ZnIn2S4@CdS Nanocages for Efficient Regioselective Photocatalytic Epoxide Alcoholysis

AbstractPhotocatalytic epoxide alcoholysis through C−O bond cleavage and formation has emerged as an alternative to synthesizing anti‐tumoral pharmaceuticals and fine chemicals. However, the lack of crucial evidence to interpret the interaction between reactants and photocatalyst surface makes it challenging for photocatalytic epoxide alcoholysis with both high activity and regioselectivity. In this work, we report the hierarchical ZnIn2S4@CdS photocatalyst for epoxide alcoholysis with high regioselectivity nearly 100 %. Mechanistic studies unveil that the precise activation switch on exposed Zn acid sites for C−O bond polarization and cleavage has a critical significance for achieving efficient photocatalytic performance. Furthermore, the establishment of Z‐scheme heterojunction facilitates the interface charge separation and transfer. Remarkably, the underlying regioselective photocatalytic reaction pathway has been distinctly revealed.

Exposed Zinc Sites on Hybrid ZnIn2 S4 @CdS Nanocages for Efficient Regioselective Photocatalytic Epoxide Alcoholysis.

Photocatalytic epoxide alcoholysis through C-O bond cleavage and formation has emerged as an alternative to synthesizing anti-tumoral pharmaceuticals and fine chemicals. However, the lack of crucial evidence to interpret the interaction between reactants and photocatalyst surface makes it challenging for photocatalytic epoxide alcoholysis with both high activity and regioselectivity. In this work, we report the hierarchical ZnIn2 S4 @CdS photocatalyst for epoxide alcoholysis with high regioselectivity nearly 100 %. Mechanistic studies unveil that the precise activation switch on exposed Zn acid sites for C-O bond polarization and cleavage has a critical significance for achieving efficient photocatalytic performance. Furthermore, the establishment of Z-scheme heterojunction facilitates the interface charge separation and transfer. Remarkably, the underlying regioselective photocatalytic reaction pathway has been distinctly revealed.

Regioselective C-H Active Carbonylation via 1,4-Palladium Migration.

We report a highly regioselective three-component coupling reaction of styrene, CO gas, and an amine compound to synthesize multisubstituted α,β-unsaturated amides, which involves a palladium-catalyzed sequential 1,4-palladium migration, C(sp2)-H activation, carbonylation, and amination. Salient features of this strategy include the use of 1 atm of CO, excellent stereochemistry, and good functional group tolerance. Further, a series of control experiments and density functional theory calculations were performed to afford some insights for the transfer mechanism.

Stereoselective and regioselective Heck arylation at C-17 exocyclic double bond of andrographolide to generate labdane-based lead molecule against acute lung injury

Andrographolide (AG-1) is identified as an attractive scaffold based on in silico/in vitro/in vivo (preclinical and clinical) studies against COVID-19 infection, for which hardly any effective drug is available to date. Due to complexity of its chemical structure, stereoselective and regioselective Heck arylation reactions at C-17 exocyclic double bond of AG-1 is a major challenge and we stepped forward to generate a small focused library of compounds. Among all the molecules, AG-12 and AG-13 were predicted to have better pharmacokinetic profiles than AG-1. Upon evaluation of in vivo efficacy of AG-12 and AG-13 in comparison to AG-1 using an LPS-induced acute lung injury model, AG-13 showed promising action towards reduction of the neutrophil count, minimization of oxidative stress, and inhibition of inflammatory cytokines. Further, lead optimization should be carried out towards developing potential natural product-driven therapeutics to combat acute respiratory distress syndrome (ARDS) situations during COVID-19.

Regioselective Reaction of 2-Indolylmethanols with Enamides.

A highly regioselective reaction of 2-indolylmethanols with enamides has been developed at room temperature by using AlCl3 as a catalyst. A wide range of hybrids (40 examples) of indoles and enamides were obtained in moderate to good yields (up to 98% yield). This transformation represents the efficient way to introduce biologically important indoles and enamides skeleton into structurally complex hybrids.

Three-Component Electrochemical Aminoselenation of 1,3-Dienes

Azoles and organoselenium compounds are pharmacologically important scaffolds in medicinal chemistry and natural products. We developed an efficient regioselective electrochemical aminoselenation reaction of 1,3-dienes, azoles, and diselenide derivatives to access selenium-containing allylazoles skeletons. This protocol is more economical and environmentally friendly and features a broad substrate scope; pyrazole, triazole, and tetrazolium were all tolerated under the standard conditions, which could be applied to the expedient synthesis of bioactive molecules and in the pharmaceutical industry.

Regiospecific Alkene Aminofunctionalization via an Electrogenerated Dielectrophile.

Modular strategies to rapidly increase molecular complexity have proven immensely synthetically valuable. In principle, transformation of an alkene into a dielectrophile presents an opportunity to deliver two unique nucleophiles across an alkene. Unfortunately, the selectivity profiles of known dielectrophiles have largely precluded this deceptively simple synthetic approach. Herein, we demonstrate that dicationic adducts generated through electrolysis of alkenes and thianthrene possess a unique selectivity profile relative to more conventional dielectrophiles. Specifically, these species undergo a single and perfectly regioselective substitution reaction with phthalimide salts. This observation unlocks an appealing new platform for aminofunctionalization reactions. As an illustrative example, we implement this new reactivity paradigm to address a longstanding synthetic challenge: alkene diamination with two distinct nitrogen nucleophiles. Studies into the mechanism of this process reveal a key alkenyl thianthrenium salt intermediate that controls the exquisite regioselectivity of the process and highlight the importance of proton sources in controlling the reactivity of alkenyl sulfonium salt electrophiles.

β-Boron Effect Enables Regioselective and Stereospecific Electrophilic Addition to Alkenes.

Electrophilic addition to alkenes is a textbook-taught reaction, yet it is not always possible to control the regioselectivity of addition to unsymmetrical 1,2-disubstituted substrates. We report the observation and applications of the β-boron effect that accounts for high regioselectivity in electrophilic addition reactions to allylic MIDA (N-methyliminodiacetic acid) boronates. While the well-established β-silicon effect bears partial resemblance to the observed reactivity, the silyl group is typically lost during functionalization. In contrast, the boryl moiety is retained in the product when B(MIDA) is used as the nucleophilic stabilizer. Mechanistic studies elucidate the origin of this effect and demonstrate how σ(C-B) hyperconjugation helps stabilize the incipient carbocation. This transformation represents a rare example of the stereospecific hydrohalogenation of secondary allyl MIDA-boronates that proceeds in a syn-fashion.

Reactivity and Selectivity of the Diels-Alder Reaction of Anthracene in [Pd6L4]12+ Supramolecular Cages: A Computational Study.

The field of supramolecular metal-organic cage catalysis has grown rapidly in recent years. However, theoretical studies regarding the reaction mechanism and reactivity and selectivity controlling factors for supramolecular catalysis are still underdeveloped. Herein, we demonstrate a detailed density functional theory study on the mechanism, catalytic efficiency, and regioselectivity of the Diels-Alder reaction in bulk solution and within two [Pd6L4]12+ supramolecular cages. Our calculations are consistent with experiments. The origins of the catalytic efficiency of the bowl-shaped cage 1 have been elucidated to be the host-guest stabilization of the transition states and the favorable entropy effect. The reasons for the switch of the regioselectivity from 9,10-addition to 1,4-addition within the octahedral cage 2 were attributed to the confinement effect and the noncovalent interactions. This work would shed light on the understanding of [Pd6L4]12+ metallocage-catalyzed reactions and provide a detailed mechanistic profile otherwise difficult to obtain from experiments. The findings of this study could also aid to the improvement and development of more efficient and selective supramolecular catalysis.